title: UGT1A1 genotype-guided phase I study of irinotecan, oxaliplatin, and capecitabine.
abstract: OBJECTIVE
  We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN).
  
  
  METHODS
  Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m(2)) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD.
  
  
  RESULTS
  50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/- 278 and 350 +/- 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/- 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups.
  
  
  CONCLUSIONS
  UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Heidi A
authors.initials: HA
authors.lastname: McKean
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
authors.forename: Angelina D
authors.initials: AD
authors.lastname: Tan
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Kuffel
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Renee M
authors.initials: RM
authors.lastname: McGovern
authors.affiliation: Ohio State University, Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, (OSUCCC - James) Columbus, OH.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Axel A
authors.initials: AA
authors.lastname: Grothey
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Robert
authors.initials: R
authors.lastname: McWilliams
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, MN.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000099148:UGT1A1 Enzyme